1,3-Dipolar Cycloaddition Reactions of trans-2-methylene-1,3-dithiolane 1,3-Dioxide with Nitrones

Full text of DOI:10.1021/jo972052l

J . Org. Chem. 1998, 63, 3481-3485
3481
1,3-Dip ola r Cycloa d d ition Rea ction s of
tr a n s-2-Meth ylen e-1,3-d ith iola n e
1,3-Dioxid e w ith Nitr on es
Varinder K. Aggarwal,*,† Richard S. Grainger,†
Harry Adams,‡ and Peter L. Spargo§
F igu r e 1.
Department of Chemistry, University of Sheffield,
Sheffield S3 7HF, UK, Crystallographic Department,
University of Sheffield, Sheffield S3 7HF, UK, and
Process R&D Department, Pfizer Central Research,
Sandwich, Kent CT13 9NJ , UK
Received November 7, 1997
F igu r e 2.
The 1,3-dipolar cycloaddition reaction between a ni-
trone and an olefinic dipolarophile is an efficient method
for the synthesis of the isoxazolidine ring system (Figure
1).1 Furthermore, the cycloadducts have found numerous
applications in synthesis through reductive cleavage of
the N-O bond to give γ-amino alcohols.1 Asymmetric
induction in nitrone-olefin cycloadditions has been
achieved through incorporation of chirality in both the
dipole and dipolarophile.2,3 More recently, advances have
been made in the use of metals to influence the rate,
regioselectivity, stereoselectivity, and enantioselectivity
of the reaction through suitable combinations of metal/
dipole/dipolarophile, effectively overcoming the tendency
of nitrones to form inactive dipole/Lewis acid complexes.4
In comparison to the Diels-Alder reaction, the 1,3-
dipolar cycloaddition of nitrones with olefins generally
exhibits lower levels of regio- and stereocontrol (exo/endo
selectivity), a consequence of significant contributions by
both LUMO (dipole)-HOMO (dipolarophile) and HOMO
(dipole)-LUMO (dipolarophile) interactions, further com-
plicated by the possibility of interconversion of the
nitrone geometry in the case of acyclic nitrones.1 There-
fore, despite the advances outlined above, there still
remains a need to develop general systems that give
predictably high levels of regio- and stereocontrol with a
range of nitrones. Herein we describe one potential
solution to this problem.
We have recently reported an asymmetric synthesis
of the C2-symmetric cyclic alkenyl sulfoxide (1R,3R)-2-
methylene-1,3-dithiolane 1,3-dioxide 1 (Figure 2).5 The
presence of a C2 symmetry element in 1 means that the
exo/endo approaches of 1 to a diene are symmetry related
and therefore identical, thereby reducing the number of
competing transition states in the reaction. Indeed, 1
showed very high reactivity and stereoselectivity in
Diels-Alder reactions with a range of dienes, and after
hydrolysis of the bis-sulfoxide moiety of the cyclopenta-
diene adduct 2, enantiomerically pure norbornenone 3
was obtained. Thus, we were able to demonstrate 1 to
be an effective chiral ketene equivalent.5 To the best of
our knowledge the potential advantage of using a C2-
symmetric dipolarophile to overcome the exo/endo issue
in 1,3-dipolar cycloaddition chemistry has not been
exploited. We report herein our results of the cycload-
dition of 1 with some acyclic and cyclic nitrones.
(3) Recent examples of chiral dipolarophiles: (a) Tejero, T.; Dondoni,
A.; Rojo, I.; Mercha´n, F. L.; Merino, P. Tetrahedron 1997, 53, 3301-
3318. (b) Busque´, F.; de March, P.; Figueredo, M.; Font, J .; Monsalvatje,
M.; Virgili, A.; AÄ lvarez-Larena, AÄ .; Piniella, J . F. J . Org. Chem. 1996,
61, 8578-8585. (c) Ina, H.; Ito, M.; Kibayashi, C. J . Org. Chem. 1996,
61, 1023. (d) Pyne, S. G.; Safaei-G, J .; Skelton, B. W.; White, A. H.
Aust. J . Chem. 1995, 48, 1511-1533. (e) David, D. M.; Bakavoli, M.;
Pyne, S. G.; Skelton, B. W.; White, A. H. Tetrahedron 1995, 51, 12393-
12402. (f) Armstrong, S. K.; Collington, E. W.; Stonehouse, J .; Warren,
S. J . Chem. Soc., Perkin Trans. 1 1994, 2825-2831. (g) Saito, S.;
Ishikawa, T.; Moriwake, T. Synlett 1994, 279-281. (h) Rispens, M. T.;
Keller, E.; De Lange, B.; Zijlstra, R. W. J .; Feringa, B. L. Tetrahedron
Asymm. 1994, 5, 607-624. (i) Ito, M.; Maeda, M.; Kibayashi, C.
Tetrahedron Lett. 1992, 33, 3765-3768. (j) Carruthers, W.; Coggins,
P.; Weston, J . B. J . Chem. Soc., Chem. Commun. 1991, 117-118. (k)
Annunziata, R.; Cinquini, M.; Cozzi, F.; Giaroni, P.; Raimondi, L.
Tetrahedron Lett. 1991, 32, 1659-1662. (l) Krol, W. J .; Mao, S. S.;
Steele, D. L.; Townsend, C. A. J . Org. Chem. 1991, 56, 728-731. (m)
Brandi, A.; Cicchi, S.; Goti, A.; Pietrusiewicz, K. M.; Zablocka, M.;
Wisniewski, W. J . Org. Chem. 1991, 56, 4383-4388.
† Department of Chemistry.
‡ Crystallographic Department.
§ Process R&D Department.
(1) For reviews see: (a) Tufariello, J . J . Acc. Chem. Res. 1979, 12,
396-403. (b) Tufariello, J . J . In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; J ohn Wiley & Sons: New York, 1984; Vol. 2, pp 83-
168. (c) Confalone, P. N.; Huie, E. M. Org. React. (N.Y.) 1988, 36,
1-173. (d) Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates
in Organic Synthesis; VCH: New York, 1988. (e) Carruthers, W.
Cycloaddition Reactions in Organic Synthesis; Pergamon Press: Ox-
ford, 1990. (f) Padwa, A. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon: Oxford, 1991;
Vol. 4, pp 1069-1109. (g) Gru¨nanger, P.; Vita-Finzi, P. Isoxazoles; J .
Wiley & Sons: New York, 1991. (h) Frederickson, M. Tetrahedron 1997,
53, 403-425.
(2) Recent examples of chiral dipoles: (a) Katagiri, N.; Okada, M.;
Morishita, Y.; Kaneko, C. Tetrahedron 1997, 53, 5725-5746. (b)
Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi, M.; Miyawaki, T.;
Sakamoto, M. J . Chem. Soc. Chem. Commun. 1996, 1861-1862. (c)
van den Broek, L. A. G. M. Tetrahedron 1996, 52, 4467-4478. (d) Goti,
A.; Cardona, F.; Brandi, A.; Picasso, S.; Vogel, P. Tetrahedron Asymm.
1996, 7, 1659-1674. (e) Goti, A.; Cardona, F.; Brandi, A. Synlett 1996,
761-763. (f) De March, P.; Figueredo, M.; Font, J .; Gallagher, T.;
Milan, S. J . Chem. Soc., Chem. Commun. 1995, 2097-2098. (g) Cicchi,
S.; Goti, A.; Brandi, A. J . Org. Chem. 1995, 60, 4743-4748. (h)
Oppolzer, W.; Deerberg, J .; Tamura, O. Helv. Chim. Acta 1994, 77,
554-560. (i) Brandi, A.; Cicchi, S.; Goti, A.; Koprowski, M.; Pi-
etrusiewicz, K. M. J . Org. Chem. 1994, 59, 1315-1318. (j) Saito, S.;
Ishikawa, T.; Kishimoto, N.; Kohara, T.; Moriwake, T. Synlett 1994,
282-284. (k) Brandi, A.; Cicchi, S.; Goti, A.; Pietrusiewicz, K. M.
Tetrahedron Asymm. 1991, 2, 1063-1074.
(4) (a) Hori, K.; Kodama, H.; Ohta, T.; Furukawa, I. Tetrahedron
Lett. 1996, 37, 5947-5950. (b) Gothelf, K. V.; Hazell, R. G.; J orgensen,
K. A. J . Org. Chem. 1996, 61, 346-355. (c) Gothelf, K. V.; Thomsen,
I.; J orgensen, K. A. J . Am. Chem. Soc. 1996, 118, 59-64. (d) Gilbertson,
S. R.; Dawson, D. P.; Lopez, O. D.; Marshall, K. L. J . Am. Chem. Soc.
1995, 117, 4431-4432. (e) Kanemasa, S.; Tsuruoka, T.; Yamamoto,
H. Tetrahedron Lett. 1995, 36, 5019-5022. (f) Seerden, J . P. G.; Reimer,
A.; Scheeren, H. W. Tetrahedron Lett. 1994, 35, 4419-4422. (g) Gothelf,
K. V.; J orgensen, K. A. J . Org. Chem. 1994, 59, 5687-5691. (h) Mukai,
C.; Kim, I. J .; Cho, W. J .; Kido, M.; Hanaoka, M. J . Chem. Soc., Perkin
Trans. 1 1993, 2495-2503. (i) Kanemasa, S.; Tsuruoka, T.; Wada, E.
Tetrahedron Lett. 1993, 34, 87-90. (j) Murahashi, S. I.; Imada, Y.;
Kohno, M.; Kawakami, T. Synlett 1993, 395-396. (k) Kanemasa, S.;
Uemura, T.; Wada, E. Tetrahedron Lett. 1992, 33, 7889-7892.
(5) Aggarwal, V. K.; Drabowicz, J .; Grainger, R. S.; Gultekin, Z.;
Lightowler, M.; Spargo, P. L. J . Org. Chem. 1995, 60, 4962-4963.
S0022-3263(97)02052-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/28/1998

3482 J . Org. Chem., Vol. 63, No. 10, 1998
Notes
Sch em e 1a
a
Reagents and conditions: (i) HSCH2CH2SH, concd HCl, rt, 6 h (91%); (ii) m-CPBA, Et2O, 0 °C, 2 h (84%); (iii) Me2NH, MeCN, rt, 24
h (100%); (iv) MeI, i-Pr2NEt, MeCN, rt, 18 h (86%).
Sch em e 2
Racemic 1 was readily prepared in four steps as
outlined in Scheme 1. Transthioketalization of the com-
mercially available acetal 4 with 1,2-ethanedithiol under
acid catalysis6 gave the methoxymethyl-substituted 1,3-
dithiolane 5 in high yield. Oxidation of 5 using m-CPBA
in Et2O7 gave exclusively the trans bis-sulfoxide 6 which
could be isolated and purified by simple filtration and
recrystallization. Compound 6 was smoothly converted
to the dimethylamino-derivative 7 simply by stirring in
a solution of dimethylamine in acetonitrile at room
temperature.5 Finally, Hofmann elimination using meth-
yl iodide and Hu¨nig’s base at room temperature gave 1
in 86% isolated yield.5
Ta ble 1. 1,3-Dip ola r Cycloa d d ition betw een 1 a n d
Acyclic Nitr on es
entry
nitronea
nitrone adduct
time
isolated yield, %
1
2
3
8
9
10
11
12
13
48
15
13
77
64
86
At the outset of this work it was not clear what the
regiochemical preference for the cycloaddition of 1 with
nitrones would be. Although vinyl sulfoxides appear to
exclusively favor formation of isoxazolidines with the
sulfur functionality incorporated at C-4,8,9 1,1-disubsti-
tuted olefins predominately yield isoxazolidines disub-
stituted at C-5, the regiochemical preference being
influenced more by the substitution pattern on the olefin
than by the electronic nature of the substituents.10 It
was therefore gratifying to observe that the cycloaddition
of 1 with the commercially available N-tert-butyl-C-
phenyl nitrone 8 proceeded readily in dichloromethane
at room temperature using 5 equiv of nitrone (the excess
nitrone could be recovered) to give a single diastereomeric
4,4-disubstituted isoxazolidine product 11 in 77% isolated
a
All reactions were conducted in dichloromethane at room
temperature using 5 equiv of nitrone.
yield (Scheme 2, Table 1, entry 1).11,12 Reaction of 1 with
N,C-diphenyl nitrone 9 and N-methyl-C-phenyl nitrone
10 proceeded more readily, presumably due to the
reduced steric hindrance in these nitrones, to again give
single diastereomeric 4-substituted isoxazolidine prod-
ucts 12 and 13, respectively (Table 1, entries 2, 3).11
The stereochemistry of the N-methyl adduct 13 was
determined by X-ray crystallography.13 The observed
stereoselectivity can be rationalized by considering the
possible transition states for the reaction (Figure 3). Due
to the C2-symmetry element present in the dipolarophile,
only two transition states are possible, leading to the
diastereomeric 4-substituted isoxazolidines 13 and 14.
Transition state TS 1 leads to the observed product 13.
The alternative transition state TS 2 suffers from steric
and/or electronic repulsions between the phenyl ring of
the nitrone and the sulfinyl oxygen; in transition state
TS 1 the phenyl group approaches over a sulfinyl lone-
pair and the oxygen of the second sulfoxide over the
smaller hydrogen atom (Figure 3).5
(6) Dahnke, K. R.; Paquette, L. A. Org. Synth. 1992, 71, 175-180.
(7) (a) Aggarwal, V. K.; Davies, I. W.; Franklin, R.; Maddock, J .;
Mahon, M. F.; Molloy, K. C. J . Chem. Perkin Trans. 1, 1994, 2363-
2368. (b) Aggarwal, V. K.; Schade, S.; Adams, H. J . Org. Chem. 1997,
62, 1139-1145.
(8) (a) Koizumi, T.; Hirai, H.; Yoshii, E. J . Org. Chem. 1982, 47,
4004-4005. (b) Takahashi, T.; Fujii, A.; Sugita, J .; Hagi, T.; Kitano,
K.; Arai, Y.; Koizumi, T.; Shiro, M. Tetrahedron Asymm. 1991, 2, 1379-
1390. (c) Bravo, P.; Bruche, L.; Farina, A.; Fronza, G.; Meille, S. V.;
Merli, A. Tetrahedron Asymm. 1993, 4, 2131-2134. (d) Louis, C.;
Hootele´, C. Tetrahedron Asymm. 1995, 6, 2149-2152. (e) Garcia Ruano,
J . L.; Fraile, A.; Martin, M. R. Tetrahedron Asymm. 1996, 7, 1943-
1950. (f) Louis, C.; Hootele´, C. Tetrahedron Asymm. 1997, 8, 109-
131.
(9) Acetylenic sulfoxides and allenyl sulfoxides exhibit the same
regiochemical preference. Acetylenic sulfoxides: (a) Louis, C.; Mill, S.;
Mancuso, V.; Hootele´, C. Can. J . Chem. 1994, 72, 1347-1350. (b)
Macours, P.; Braekman, J . C.; Daloze, D. Tetrahedron 1995, 51, 1415-
1428. Allenyl sulfoxides: Padwa, A.; Norman, B. H.; Perumattam, J .
Tetrahedron Lett. 1989, 30, 663-666.
The stereochemical course of the N-phenyl and N-tert-
butyl nitrone cycloadditions would be expected to follow
a similar pattern. The stereochemistry of isoxazolidines
11 and 12 have thus been assigned by analogy with 13.14
Simple cyclic nitrones are another well-known and
frequently studied class of 1,3-dipole. Selectivities in
cycloadditions are often much higher than with acyclic
(10) (a) Reference 1. (b) For an example see: Keirs, D.; Moffat, D.;
Overton, K.; Tomanek, R. J . Chem. Soc., Perkin Trans. 1 1991, 1041-
1051. (c) Brandi has frequently observed significant amounts of the
4-substituted isomer in his use of methylene cyclopropanes as dipo-
larophiles in 1,3-dipolar cycloadditions: Brandi, A.; Cordero, F. M.;
De Sarlo, F.; Goti, A.; Guarna, A. Synlett 1993, 1-8. Attempts to
rationalise this selectivity by an FMO treatment gave unsatisfactory
results: Brandi, A.; Cordero, F. M.; Desarlo, F.; Gandolfi, R.; Rastelli,
A.; Bagatti, M. Tetrahedron 1992, 48, 3323-3334. There are a few
examples of the nitrone cycloaddition of 1,1-disubstituted alkenes
bearing electron-withdrawing groups (diethyl methylenemalonate).
Selective formation of 4,4-disubstituted isoxazolidines is observed with
N,C-diphenyl nitrone and with 2,3,4,5-tetrahydropyridine 1-oxide but
N-methyl nitrone gives the 5,5-disubstituted isoxazolidine instead.
See: Ali, S. A.; Senaratne, P. A.; Illig, C. R.; Meckler, H.; Tufariello,
J . J . Tetrahedron Lett. 1979, 20, 4167-4170.
(11) No other adduct could be detected by TLC or in the crude NMR
of the reaction mixture.
(12) Yields of nitrone cycloadducts have not been optimized.
(13) The author has deposited atomic coordinates for 13 and 19a
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
(14) This transition state argument assumes nitrones 8-10 react
through their Z-form, as they exist at the reaction temperature.
However, the same major product could also be obtained via an
E-nitrone and applying a similar argument. Although the nitrones
would not be expected to interconvert between Z- and E-forms at room
temperature, the greater reactivity of E-nitrones over Z-nitrones means
that the possibility of this interconversion during the reaction cannot
be ignored. See for example ref 3h.

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3483
F igu r e 3.
F igu r e 5.
Ta ble 2. 1,3-Dip ola r Cycloa d d ition betw een 1 a n d Cyclic
Nitr on es
a 22:1 mixture of diastereomers (entry 1). Similarly, the
diastereomeric ratio obtained from reaction of nitrone 16
with 1 could be increased from 10:1 at room temperature
to 20:1 at -78 °C (entry 2). 1 underwent completely
regio- and stereoselective cycloaddition with the iso-
quinoline-derived nitrone 17 (entry 3). The stereochem-
istry of isoxazolidine 20 (and of the major adduct 18a )
was assigned as shown by analogy with 19a (vide infra,
vide supra).
ratio of
nitrone adducts isolated
entry nitronea T (°C)
time
adducts
(a :b)b
yield, %
1
2
3
15
16
17
-78
-78
rt
60 min 18a :18b
60 min 19a :19b
22:1
20:1
-
84
75
81
48 h
20
a
All reactions were conducted in dichloromethane using 5 equiv
of nitrone. Determined by 1H NMR integration of crude reaction
b
mixtures.
Slow recrystallization of a mixture of 19a and 19b
allowed for the unambiguous determination of the struc-
ture of the major adduct 19a by X-ray crystallography.13
Based upon this crystal structure, a stereochemical
rationale can again be proposed. The two possible
transition states leading to the two diastereomeric isox-
azolidines 19a and 19b are shown in Figure 5. To
account for the observed selectivity, transition state TS
3 must be favored over transition state TS 4. Presum-
ably the unfavorable steric interactions in TS 3 are even
more pronounced in TS 4, where the “offending” oxygen
approaches over the bulk, rather than the periphery, of
the nitrone ring. The higher selectivity observed in the
case of 17 may be due to an additional electronic
repulsion in transition state TS 4 between the sulfinyl-
oxygen lone pair and the π-system of the aromatic ring.5
F igu r e 4.
nitrones due to the absence of E-Z isomerization in the
dipole. Furthermore, with nonconjugated monosubsti-
tuted olefins, reactions have been shown to proceed
preferentially via exo-transition states affording trans-
adducts; endo-transition states are disfavored by steric
interactions of substituents on the dipolarophile with
methylene groups on the ring.1 It was of interest
therefore to investigate how a 1,1-disubstituted dipolaro-
phile such as 1, in which one substituent must always
interact to some extent with the dipole ring, would react
with such nitrones.
In conclusion we have reported that the C2-symmetric
dipolarophile 1 adds to both acyclic and cyclic nitrones
with very high stereoselectivity. In addition, the 1,3-
dipolar cycloaddition of 1 with nitrones is a rare example
of a 1,1-disubstituted olefin reacting regioselectively to
give 4,4- rather than 5,5-disubstituted isoxazolidines.
Exp er im en ta l Section
Gen er a l. m-CPBA was purified by washing an ether solution
of commercially available material (57-86%) four times with a
phosphate buffer, followed by drying and careful removal of
solvent. Nitrone 10 was prepared by the condensation of
N-methylhydroxylamine and benzaldehyde according to the
method of DeShong.15 Nitrones 15-17 were prepared in one
step from the corresponding amine through treatment with
hydrogen peroxide in the presence of a tungstate catalyst
according to Murahashi.16 All other reagents are commercially
available and were used as received.
The results of the 1,3-dipolar cycloaddition of 1 with
nitrones 15-17 are summarized in Table 2. Reaction
with the pyrrolidine-derived nitrone 15 occurred readily
at room-temperature giving a 10:1 mixture of 18a :18b
(Figure 4). Assignment of the minor isomer as diaste-
reomer 18b rather than a regioisomer was based upon
the NMR of the (inseparable) mixture of cycloadducts.
The geminal protons of the isoxazolidine ring appear as
simple doublets for both major and minor products. The
greater reactivity of the cyclic nitrones over their acyclic
counterparts allowed this reaction to occur at lower
temperature. After only 60 min at -78 °C, all alkene 1
had been consumed, and the cycloadduct was isolated as
(15) Dicken, C. M.; DeShong, P. J . Org. Chem. 1982, 47, 2047-2051.
(16) (a) Murahashi, S. I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe,
S. J . Org. Chem. 1990, 55, 1736-1744. (b) Murahashi, S. I.; Shiota,
T.; Imada, Y. Org. Synth. 1991, 70, 265-271.

3484 J . Org. Chem., Vol. 63, No. 10, 1998
Notes
2-(Meth oxym eth yl)-1,3-d ith iola n e (5). A 1 L three-necked
RB flask equipped with a 250 cm3 pressure-equalizing dropping
funnel, thermometer, and overhead stirrer was charged with 1,2-
ethanedithiol (91 cm3, 1.095 mol) and concentrated hydrochloric
acid (77 cm3). The mixture was cooled to 0 °C, and 2-methoxy-
acetaldehyde dimethyl acetal 4 (131 cm3, 1.03 mol) was slowly
added via the dropping funnel over 1.5 h, ensuring the temper-
ature did not rise above 10 °C. The reaction mixture was stirred
for a further 1 h at 0 °C and then 3 h at room temperature. The
reaction mixture was partitioned between dichloromethane (200
cm3) and H2O (200 cm3), the organic phase separated, and the
aqueous phase extracted with more dichloromethane (200 cm3).
Combined organics were washed with water (200 cm3), saturated
NaHCO3 solution (300 cm3), and brine (200 cm3) and dried over
MgSO4, and solvent was removed under reduced pressure.
Distillation of the liquid residue gave the title compound as a
colorless liquid (140.5 g, 91%), bp 54-55 °C (0.15 mmHg),
(Found: C, 39.6; H, 6.8; S, 43.1%. C5H10S2O requires C, 40.0;
H, 6.7; S, 42.7%); υmax(thin film)/cm-1 2980-2820; 1H NMR (250
MHz; CDCl3) δ 3.19 (4H, s), 3.39 (3H, s); 3.47 (2H, d, J ) 7) and
4.58 (1H, t, J ) 7); 13C NMR (63 MHz; CDCl3) δ 38.0, 51.4, 48.9
and 77.6; m/z (EI) 150 (M+, 100%).
(1RS,3RS)-2-(Meth oxym eth yl)-1,3-d ith iola n e 1,3-Dioxid e
(6). 1,3-Dithiolane 5 (15.99 g, 106 mmol) was dissolved in dry
ether (300 cm3) and the temperature reduced to 0 °C. A solution
of purified m-CPBA (40 g, 232 mmol) in dry ether (400 cm3) was
added dropwise over 1 h, and then the reaction mixture was
stirred for a further 1 h at 0 °C. The resulting white precipitate
was filtered and washed with cold ether. Recrystallization from
hot ethyl acetate gave white crystals of the title compound (16.13
g, 84%), Rf 0.3 (10% MeOH/EtOAc), mp 124-125 °C (EtOAc),
(Found: C, 32.8; H, 5.3; S, 35.3%. C5H10S2O3 requires C, 32.95;
H, 5.5; S, 35.2%); υmax(KBr)/cm-1 2975-2830 and 1020 (SdO);
1H NMR (300 MHz; CDCl3) δ (single diastereomer) 3.43 (3H, s),
3.60-3.82 (4H, m) and 3.90-4.10 (3H, m); δC (63 MHz; CDCl3)
51.3 and 51.8, 59.5, 64.2 and 89.5; m/z (EI) 183 (MH+, 100%).
(1RS,3RS)-2-[(Dim eth ylam in o)m eth yl]-1,3-dith iolan e 1,3-
Dioxid e (7). (1RS,3RS)-2-(Methoxymethyl)-1,3-dithiolane 1,3-
dioxide 6 (1.44 g, 7.92 mmol) was dissolved in a solution of
dimethylamine in acetonitrile (25 cm3, 0.3 M) at room temper-
ature. The solution was stirred in the dark for 24 h, after which
time acetonitrile, excess dimethylamine, and liberated methanol
were evaporated under reduced pressure to give the title
compound as an off white solid (1.54 g, 100%), Rf 0.3 (5% MeOH/
acetone), mp 105.5-106.5 °C(t-BuOAc); (Found: C, 36.8; H, 6.9;
N, 7.2; S, 32.5%. C6H13NS2O2 requires C, 36.9; H, 6.7; N, 7.2;
S, 32.8%); υmax(KBr)/cm-1 1028 (SdO); 1H NMR (250 MHz;
CDCl3) δ 2.37 (6H, s), 2.91 (2H, d, J ) 8.5), 3.50-3.83 (4H, m)
and 3.92 (1H, td, J ) 8.5 and 0.6); 13C NMR (63 MHz; CDCl3) δ
45.5, 50.8, 51.3 and 52.1 and 90.5; m/z (EI) 195 (M+, 24%), 118
(55) and 58 (100).
phenyl nitrone 8 (354 mg, 2 mmol) was added in one portion to
a solution of alkene 1 (59 mg, 0.4 mmol) in dry dichloromethane
(0.8 cm3) at room temperature under nitrogen. After stirring
for 48 h, the reaction mixture was columned directly, eluting
with ethyl acetate. The excess nitrone eluted first, followed by
the title compound as a white solid (99 mg, 77%), Rf 0.5 (EtOAc),
mp 149.5-150 °C (EtOAc), (Found: C, 55.0; H, 6.4; N, 4.4; S,
19.7%. C15H21S2O3N requires C, 55.0; H, 6.5; N, 4.3; S, 19.6%);
υ
max(KBr)/cm-1 3063-2868, 1051 and 1032 (SdO); 1H NMR (250
MHz; CDCl3) δ 1.08 (9H, s), 3.24 (1H, dt, J ) 14 and 4.5), 3.34
(1H, ddd, J ) 14, 4.5 and 2), 3.69 (1H, ddd, J ) 14, 4.5 and 2),
3.82 (1H, dt, J ) 14 and 4.5); 3.99 (1H, d, J ) 11.5), 4.61 (1H,
d, J ) 11.5), 4.93 (1H, s), 7.96 (1H, br d, J ) 7.5) and 7.01-7.49
(4H, m); 13C NMR (63 MHz; CDCl3) δ 26.2, 50.9, 51.3, 59.7, 61.0,
67.9, 103.1, 127.3, 128.3, 128.7, 129.1, 129.2 and 138.8; m/z (EI)
327 (M+, 9), 310 (12), 254 (17), 250 (15), 194 (100), 146 (19), 115
(21), 104 (41), 77 (27) and 57 (64%); (Found: M+, 327.0957.
C15H21S2O3N requires m/z, 327.0963).
(1RS,3RS,3′RS)-2′,3′-Dip h en ylsp ir o[(1,3-d ith iola n e)-2,4′-
isoxa zolid in e] 1,3-Dioxid e (12). N,C-Diphenyl nitrone 9 (483
mg, 2.45 mmol) was added in one portion to a solution of alkene
1 (71.4 mg, 0.47 mmol) in dry dichloromethane (0.95 cm3) at
room temperature under nitrogen. After stirring the resulting
suspension for 15 h, the white solid (undissolved nitrone) was
filtered and the filtrate evaporated under reduced pressure.
Column chromatography, eluting with ethyl acetate, gave excess
nitrone, followed by the title compound as an off-white solid
(105.3 mg, 64%), Rf 0.4 (EtOAc), mp 139-140 °C (yellow crystals,
EtOAc/40-60 petroleum ether), (Found: C, 58.6; H, 4.9; N, 4.1;
S, 18.5%.
C17H17S2O3N requires C, 58.8; H, 4.9; N, 4.0; S,
18.45%); υmax(KBr)/cm-1 3060-2937, 1596, 1488, 1038; 1H NMR
(250 MHz; CDCl3) δ 3.24-3.45 (2H, m), 3.61-3.78 (2H, m), 4.29
(1H, d, J ) 11), 4.86 (1H, d, J ) 11), 5.37 (1H, s), 6.98-7.07
(3H, m), 7.20-7.44 (5H, m) and 7.56-7.64 (2H, m); 13C NMR
(63 MHz; CDCl3) δ 51.2, 51.3, 67.6, 68.8, 102.7, 116.3, 123.5,
128.1, 128.9, 129.0, 129.2, 135.5 and 148.6; m/z (EI) 347 (M+,
7), 330 (5), 270 (53), 223 (19), 193 (21), 180 (100), 149 (63) and
77 (52%); (Found: M+, 347.0642. C17H17S2O3N requires m/z,
347.0650).
(1RS,3RS,3′RS)-2′-Meth yl-3′-ph en ylspir o[(1,3-dith iolan e)-
2,4′-isoxa zolid in e] 1,3-Dioxid e (13). N-Methyl-C-phenyl ni-
trone 10 (2.391 g, 17.7 mmol) was added in one portion to a
solution of alkene 1 (539 mg, 3.6 mmol) in dry dichloromethane
(7.2 cm3) at room temperature under nitrogen. After stirring
for 13 h the reaction mixture was subjected to column chroma-
tography on silica gel, eluting with ethyl acetate. The title
compound was obtained as a white solid (879 mg, 86%), Rf 0.4
(EtOAc), mp 140-140.5 °C (EtOAc), (Found: C, 50.1; H, 5.2; N,
4.95; S, 22.3%. C12H15S2O3N requires C, 50.5; H, 5.3; N, 4.9; S,
22.5%); υmax(KBr)/cm-1 3056-2932, 1491, 1054 and 1030; 1H
NMR (250 MHz; CDCl3) δ 2.74 (3H, s), 3.09 (1H, dt, J ) 14 and
5), 3.37 (1H, ddd, J ) 14, 4 and 2), 3.64 (1H, ddd, J ) 14, 5 and
2), 3.76 (1H, dt, J ) 14 and 4), 4.09 (1H, d, J ) 11), 4.39 (1H, s),
4.65 (1H, d, J ) 11), 7.25-7.38 (3H, m) and 7.46-7.56 (2H, m);
13C NMR (63 MHz; CDCl3) δ 42.9, 51.4, 51.7, 68.4, 72.3, 99.9,
128.7, 128.9, 129.0, and 132.5; m/z (EI) 285 (M+, 8), 268 (25),
208 (63), 134 (25), 118 (100) and 77 (43%); (Found: M+, 285.0489.
(1RS,3RS)-2-Meth ylen e-1,3-d ith iola n e 1,3-Dioxid e (1).
Amine 7 (531.6 mg, 2.72 mmol) was dissolved in dry acetonitrile
(5.4 cm3) at room temperature under nitrogen. N,N-Diisopro-
pylethylamine (0.95 cm3, 5.44 mmol) was added followed by
methyl iodide (0.85 cm3, 13.61 mmol). After 2 min the reaction
mixture turned cloudy. The solution was stirred at room
temperature for a further 18 h. Dry EtOAc (11 cm3) was then
added and the reaction mixture filtered. The precipitate (di-
isopropylethylmethylammonium iodide and tetramethylammo-
nium iodide) was washed with more EtOAc (4 × 5.5 cm3) and
the filtrate evaporated under reduced pressure. Flash column
chromotography on Sorbsil silica17 C60 (40-60 um), eluting with
acetone, gave diisopropylethylammonium iodide followed by the
title compound as a white solid (351.4 mg, 86%), Rf 0.4 (5%
MeOH/acetone), (Found: C, 32.2; H, 4.0%; S, 42.4. C4H6S2O2
requires C, 32.0; H, 4.0; S, 42.6%); υmax(KBr)/cm-11630 and 1030;
1H NMR (250 MHz; CDCl3) δ 3.60-3.82 (4H, m) and 6.91 (2H,
s); δC (63 MHz, CDCl3) 51.4, 135.4 and 165; m/z (EI) 150 (M+,
47%), 122 (23), 108 (43) and 58 (100).
C
12H15S2O3N requires m/z, 285.0493).
(1RS,3RS,3a ′RS)-Sp ir o[(1,3-d ith iola n e)-2,3′-p er h yd r op y-
r r olo[1,2-b]isoxa zole] 1,3-Dioxid e (18a ). Alkene 1 (64 mg,
0.43 mmol) was added to a solution of 1-pyrroline N-oxide 15
(180 mg, 2.1 mmol) in dry dichloromethane (0.84 cm3) at -78
°C under nitrogen. After stirring for 1 h, the solution was
allowed to warm to room temperature. Column chromatography
of the reaction mixture, eluting with neat acetone, gave cycload-
ducts 18a and 18b together as an approximately 22:1 mixture
of diastereomers (74 mg, 75%). Recrystallization from ethyl
acetate/40-60 petroleum ether gave the title compound as white
crystals (68 mg, 69%), Rf 0.4 (acetone), mp 127-128 °C (EtOAc/
40-60 petroleum ether), (Found: C, 40.8; H, 5.5; N, 6.0; S,
27.45%. C8H13S2O3N requires C, 40.8; H, 5.6; N, 5.95; S,
27.25%); υmax(KBr)/cm-1 2986-2950, 1056 and 1042; 1H NMR
(400 MHz; CDCl3) δ 1.84-1.95 (1H, m), 2.00-2.23 (3H, m), 3.13
(1H, dt, J ) 13.5 and 7.5), 3.36-3.40 (1H, ddd, J ) 13.5, 7.5
and 5), 3.45 (1H, dt, J ) 14 and 4.5), 3.57 (1H, ddd, J ) 14, 4.5
and 1.5), 3.65 (1H, ddd, J ) 14, 4.5, 1.5), 3.83 (1H, dt, J ) 14
and 4.5), 3.86 (1H, d, J ) 10.5), 4.09 (1H, t, J ) 8) and 4.50 (1H,
(1RS,3RS,3′RS)-2′-ter t-Bu t yl-3′-p h en ylsp ir o[(1,3-d it h i-
ola n e)-2,4′-isoxa zola n e] 1,3-Dioxid e (11). N-tert-Butyl-C-
(17) It is essential to use this grade silica. Merck silica gel 60, eluting
with distilled acetone, caused some decomposition and transformation
of the product into the bis-sulfoxide 6. We do not know the origin of
the methanol.

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3485
d, J ) 10.5); 13C NMR (63 MHz; CDCl3) δ 25.0, 28.5, 50.4, 51.4,
56.0, 64.7, 66.0 and 100.9; m/z (EI) 235 (M+, 14), 218 (29), 158
(100), 112 (48), 85 (24), 68 (28) and 55 (23%); (Found: M+,
235.0301. C8H13S2O3N requires m/z, 235.0337).
Peaks assignable to minor diastereomer 18b: δH (250 MHz;
CDCl3) 3.95-4.05 (1H, m), 4.41 (1H, d, J ) 10).
mmol) in dry dichloromethane (7.2 cm3) under nitrogen at room
temperature. The homogeneous orange solution was stirred for
a further 48 h and then preabsorbed onto silica gel. Column
chromatography, eluting with neat ethyl acetate, gave the title
compound as a white solid (870 mg, 81%), Rf 0.3 (EtOAc), mp
124-125 °C (EtOAc), (Found: C, 52.5; H, 5.05; N, 4.8, 21.4%.
(1RS,3RS,3a′RS)-Spir o[(1,3-dith iolan e)-2,3′-per h ydr oisox-
a zolo[2,3-a ]p yr id in e] 1,3-Dioxid e (19a ). Alkene 1 (67 mg,
0.45 mmol) was added to a solution of 2,3,4,5-tetrahydopyridine
N-oxide 16 (248 mg, 2.5 mmol) in dry dichloromethane (0.89 cm3)
at -78 °C under nitrogen. After stirring for 1 h, the solution
was allowed to warm to room temperature. Column chroma-
tography of the reaction mixture, eluting with ethanol-ethyl
acetate (1:10) gave cycloadducts 19a and 19b together as an
approximately 20:1 mixture of diastereomers (94 mg, 84%). Slow
recrystallization from CH2Cl2 gave crystals of the title compound,
Rf 0.4 (10% EtOH/EtOAc), mp 154-155 °C (EtOAc), (Found: C,
43.3; H, 5.9; N, 5.7; S, 25.6%. C9H15S2O3N requires C, 43.35;
H, 6.1; N, 5.6; S, 25.7%); υmax(KBr)/cm-1 2956-2826 and 1036;
1H NMR (400 MHz; CDCl3) δ 1.21-1.35 (1H, m), 1.57-1.90 (5H,
m), 2.56 (1H, ddd, J ) 3, 9 and 12), 2.94 (1H, dd, J ) 11.5 and
2.5), 3.46-3.58 (2H, m), 3.63-3.79 (3H, m), 3.90 (1H, d, J ) 11)
and 4.43 (1H, d, J ) 11); 13C NMR (63 MHz; CDCl3) δ 23.3, 24.2,
26.1, 51.1, 52.0, 55.5, 64.2, 70.6 and 96.6; m/z (EI) 249 (M+, 12),
232 (28), 172 (83), 150 (30), 126 (26), 108 (26), 99 (54), 82 (49),
58 (100), 55 (48%); (Found: M+, 249.0492. C9H15S2O3N requires
m/z, 249.0493).
C13H15S2O3N requires C, 52.5; H, 5.1; N, 4.7, S, 21.6%); υmax-
(KBr)/cm-1 3020 (C-H aromatic), 2967-2847, 1492, 1042; 1H
NMR (400 MHz; CDCl3) δ 2.91-3.04 (1H, m), 3.10-3.23 (2H,
m), 3.28-3.34 (1H, m), 3.46 (1H, dt, J ) 13.5 and 4), 3.53 (1H,
ddd, J ) 14, 4 and 1.5), 3.65 (1H, dt, J ) 14 and 4), 3.73 (1H,
ddd, J ) 14, 4 and 1.5), 4.08 (1H, d, J ) 11.5), 4.73 (1H, d, J )
11.5), 5.27 (1H, s), 7.13-7.26 (3H, m) and 7.46-7.50 (1H, m);
13C NMR (63 MHz; CDCl3) δ 28.7, 47.4, 51.1, 52.9, 66.3, 66.8,
99.9, 127.1, 127.6, 128.1, 128.7, 129.0 and 133.9; m/z (EI) 297
(M+, 10), 220 (6), 147 (100), 130 (23), 115 (27), 91 (40) and 58
(73%); (Found: M+, 297.0488. C13H15S2O3N requires m/z,
297.0493).
Ack n ow led gm en t. We thank Pfizer Central Re-
search, EPSRC and the DTI for a studentship (to R.G.)
via the LINK Asymmetric Synthesis Program.
Su p p or tin g In for m a tion Ava ila ble: X-ray data including
ORTEP drawing of 13 and 19a (6 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(1RS,3RS,3a ′RS)-Sp ir o[(1,3-d it h iola n e)-2,1′-1′,5′′,6′10b -
tetr a h yd r o-2′H-isoxa zolo[3,2-a ]isoqu in olin e] 1,3-Dioxid e
(20). Alkene 1 (544 mg, 3.6 mmol) was added in one portion to
a solution of 3,4-dihydroisoquinoline N-oxide 17 (2.67 g, 18.1
J O972052L